The goal of this proposal is to provide Michael Torbenson, MD with a period of mentorship in the proper scientific environment so that he can acquire the necessary skills to become an independent clinician-scientist. Dr. Torbenson has a strong background in diagnostic liver pathology and has a specific interest in viral hepatitis. This proposal focuses on occult hepatitis B, an emerging infectious entity of potentially large medical significance. Occult hepatitis B has been associated with advanced liver fibrosis, coinfection with hepatitis C, IFN alpha resistance in treatment of hepatitis C, and hepatocellular carcinoma. The overall aim of Dr. Torbenson's proposal is to assess the prevalence and clinical significance of occult hepatitis B in high risk patient population of injection drug users. This study utilizes the unique resources of a pre-existing longitudinal collection of sera and liver tissue from the mentor's ongoing research, allowing assessment of the prevalence of occult hepatitis B over time and estimation of the rate of fibrosis progression in these individuals. The first aim examines the overall prevalence of occult hepatitis B and investigates the impact of Human Immunodeficiency Virus status on the presence of occult hepatitis B. The second aim assess the clinical significance of occult hepatitis B by correlating the presence of occult hepatitis B with the amount of inflammation and fibrosis on liver biopsy. The rate of fibrosis progression will be investigated by comparing the amount of fibrosis on initial liver biopsy to that on follow-up biopsies. In addition, aim 2 will examine the role of occult hepatitis B in HIV progression. The third aim focuses on potential mechanisms of occult hepatitis B and seeks to identify relevant hepatitis B gene mutations. As a final element of this aim, carefully selected (based on known involvement in typical hepatitis B viral infection) signaling pathways will be investigated by analysis of mRNA and protein expression to investigate host-viral interactions.